PRKACA (protein kinase cAMP-activated catalytic subunit alpha)

Gene

• Entrez ID: 5566
• Gene name: Protein kinase cAMP-activated catalytic subunit alpha
• Gene symbol: PRKACA
• Synonyms: CAFD1, PKACA, PPNAD4
• Chromosome: 19
• Chromosome location: 19p13.12
• Summary: This gene encodes one of the catalytic subunits of protein kinase A, which exists as a tetrameric holoenzyme with two regulatory subunits and two catalytic subunits, in its inactive form. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. cAMP-dependent phosphorylation of proteins by protein kinase A is important to many cellular processes, including differentiation, proliferation, and apoptosis. Constitutive activation of this gene caused either by somatic mutations, or genomic duplications of regions that include this gene, have been associated with hyperplasias and adenomas of the adrenal cortex and are linked to corticotropin-independent Cushing`s syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. Tissue-specific isoforms that differ at the N-terminus have been described, and these isoforms may differ in the post-translational modifications that occur at the N-terminus of some isoforms. [provided by RefSeq, Jan 2015]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs386352352	A>C	Pathogenic, likely-pathogenic	Missense variant, coding sequence variant
rs724160013	->CAC	Pathogenic	Coding sequence variant, inframe insertion

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT030635	hsa-miR-22-3p	Sequencing	20371350
MIRT037509	hsa-miR-744-5p	CLASH	23622248
MIRT042660	hsa-miR-196b-5p	CLASH	23622248
MIRT043455	hsa-miR-331-3p	CLASH	23622248
MIRT044041	hsa-miR-365a-3p	CLASH	23622248

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000086	Process	G2/M transition of mitotic cell cycle	TAS
GO:0000287	Function	Magnesium ion binding	IEA
GO:0001669	Component	Acrosomal vesicle	ISS
GO:0001707	Process	Mesoderm formation	IEA
GO:0001843	Process	Neural tube closure	IEA
GO:0002027	Process	Regulation of heart rate	TAS	23507255
GO:0002223	Process	Stimulatory C-type lectin receptor signaling pathway	TAS
GO:0003091	Process	Renal water homeostasis	TAS
GO:0004672	Function	Protein kinase activity	IDA	12475942
GO:0004674	Function	Protein serine/threonine kinase activity	IDA	21085490
GO:0004674	Function	Protein serine/threonine kinase activity	IMP	26537248
GO:0004679	Function	AMP-activated protein kinase activity	IEA
GO:0004691	Function	CAMP-dependent protein kinase activity	IDA	11029056
GO:0004691	Function	CAMP-dependent protein kinase activity	ISS
GO:0004691	Function	CAMP-dependent protein kinase activity	NAS	2843813
GO:0004691	Function	CAMP-dependent protein kinase activity	TAS
GO:0004712	Function	Protein serine/threonine/tyrosine kinase activity	IDA	22797923
GO:0005515	Function	Protein binding	IPI	11035810, 12475942, 15630084, 15655353, 16387847, 17148597, 17911601, 18836454, 21085490, 23455922, 23602568, 24351927, 24464040, 24605759, 24700472, 24855271, 24860872, 25477193, 26496610, 27107012, 29568061, 31980649, 32296183, 32814053
GO:0005524	Function	ATP binding	IEA
GO:0005634	Component	Nucleus	HDA	21630459
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	21085490
GO:0005654	Component	Nucleoplasm	TAS
GO:0005737	Component	Cytoplasm	IDA	21085490
GO:0005739	Component	Mitochondrion	IEA
GO:0005813	Component	Centrosome	IDA	21399614
GO:0005829	Component	Cytosol	TAS
GO:0005930	Component	Axoneme	IDA	12475942
GO:0005952	Component	CAMP-dependent protein kinase complex	IDA	12475942
GO:0005952	Component	CAMP-dependent protein kinase complex	NAS	2843813
GO:0006397	Process	MRNA processing	IDA	17594903
GO:0006468	Process	Protein phosphorylation	IDA	12475942
GO:0006468	Process	Protein phosphorylation	NAS	2843813
GO:0007596	Process	Blood coagulation	TAS
GO:0010389	Process	Regulation of G2/M transition of mitotic cell cycle	TAS
GO:0010737	Process	Protein kinase A signaling	IBA	21873635
GO:0010881	Process	Regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	TAS	23507255
GO:0016020	Component	Membrane	IDA	15569306
GO:0016241	Process	Regulation of macroautophagy	TAS	26046386
GO:0016607	Component	Nuclear speck	IDA	17594903
GO:0018105	Process	Peptidyl-serine phosphorylation	IDA	10805756, 11029056
GO:0018105	Process	Peptidyl-serine phosphorylation	IMP	26537248
GO:0018105	Process	Peptidyl-serine phosphorylation	TAS	26078884
GO:0018107	Process	Peptidyl-threonine phosphorylation	IEA
GO:0019221	Process	Cytokine-mediated signaling pathway	TAS
GO:0019901	Function	Protein kinase binding	IPI	11035810, 17911601
GO:0019904	Function	Protein domain specific binding	IEA
GO:0030145	Function	Manganese ion binding	IEA
GO:0031594	Component	Neuromuscular junction	IEA
GO:0031625	Function	Ubiquitin protein ligase binding	IDA	21423175
GO:0034199	Process	Activation of protein kinase A activity	TAS
GO:0034237	Function	Protein kinase A regulatory subunit binding	IBA	21873635
GO:0034237	Function	Protein kinase A regulatory subunit binding	IPI	17911601
GO:0034380	Process	High-density lipoprotein particle assembly	TAS
GO:0034605	Process	Cellular response to heat	IDA	21085490
GO:0034704	Component	Calcium channel complex	TAS	23507255
GO:0035584	Process	Calcium-mediated signaling using intracellular calcium source	TAS	23507255
GO:0036126	Component	Sperm flagellum	IEA
GO:0043197	Component	Dendritic spine	IEA
GO:0043393	Process	Regulation of protein binding	TAS	23507255
GO:0044853	Component	Plasma membrane raft	IDA	17911601
GO:0045667	Process	Regulation of osteoblast differentiation	IDA	19949837
GO:0046777	Process	Protein autophosphorylation	IEA
GO:0046827	Process	Positive regulation of protein export from nucleus	IEA
GO:0048240	Process	Sperm capacitation	ISS
GO:0048471	Component	Perinuclear region of cytoplasm	IDA	21085490
GO:0050804	Process	Modulation of chemical synaptic transmission	IEA
GO:0051480	Process	Regulation of cytosolic calcium ion concentration	TAS	23507255
GO:0055117	Process	Regulation of cardiac muscle contraction	TAS	23507255
GO:0060314	Process	Regulation of ryanodine-sensitive calcium-release channel activity	TAS	23507255
GO:0061136	Process	Regulation of proteasomal protein catabolic process	IDA	17565987
GO:0070062	Component	Extracellular exosome	HDA	23533145
GO:0070613	Process	Regulation of protein processing	IEA
GO:0071158	Process	Positive regulation of cell cycle arrest	ISS
GO:0071333	Process	Cellular response to glucose stimulus	IDA	19949837
GO:0071374	Process	Cellular response to parathyroid hormone stimulus	IEA
GO:0071377	Process	Cellular response to glucagon stimulus	TAS
GO:0071872	Process	Cellular response to epinephrine stimulus	TAS	23507255
GO:0086064	Process	Cell communication by electrical coupling involved in cardiac conduction	TAS	23507255
GO:0097546	Component	Ciliary base	TAS
GO:0097711	Process	Ciliary basal body-plasma membrane docking	TAS
GO:1901621	Process	Negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning	IEA
GO:1903779	Process	Regulation of cardiac conduction	TAS
GO:2000810	Process	Regulation of bicellular tight junction assembly	IDA	15905176

Other IDs

• MIM: 601639
• HGNC: 9380
• e!Ensembl: ENSG00000072062

Protein

• UniProt ID: P17612
• Protein name: cAMP-dependent protein kinase catalytic subunit alpha (PKA C-alpha) (EC 2.7.11.11)
• Protein function: Phosphorylates a large number of substrates in the cytoplasm and the nucleus (PubMed:15642694, PubMed:15905176, PubMed:16387847, PubMed:17333334, PubMed:17565987, PubMed:17693412, PubMed:18836454, PubMed:19949837, PubMed:20356841, PubMed:21085490, PubMed:21514275, PubMed:21812984). Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP (PubMed:15642694, PubMed:15905176, PubMed:16387847, PubMed:17333334, PubMed:17565987, PubMed:17693412, PubMed:18836454, PubMed:19949837, PubMed:20356841, PubMed:21085490, PubMed:21514275, PubMed:21812984). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (PubMed:21423175). RORA is activated by phosphorylation (PubMed:21514275). Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts (PubMed:19949837). Involved in chondrogenesis by mediating phosphorylation of SOX9 (By similarity). Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP (PubMed:15642694, PubMed:20356841). Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated (PubMed:17333334). RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+) (PubMed:17693412). PSMC5/RPT6 activation by phosphorylation stimulates proteasome (PubMed:17565987). Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation (PubMed:15905176). NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding (PubMed:15642694). Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation (By similarity). May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). Phosphorylates APOBEC3G and AICDA (PubMed:16387847, PubMed:18836454). Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). ; [Isoform 2]: Phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation.
• PDB: 2GU8, 3AGL, 3AGM, 3AMA, 3AMB, 3L9L, 3L9M, 3L9N, 3MVJ, 3NX8, 3OOG, 3OVV, 3OWP, 3OXT, 3P0M, 3POO, 3VQH, 4AE6, 4AE9, 4UJ1, 4UJ2, 4UJ9, 4UJA, 4UJB, 4WB5, 4WB6, 4WB7, 4WB8, 5BX6, 5BX7, 5IZF, 5IZJ, 5J5X, 5N23, 5UZK, 6BYR, 6BYS, 6C0U, 6FRX, 6NO7, 6QJ7, 6WJF, 6WJG
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00069	Pkinase	44 → 298	Protein kinase domain	Domain

• Sequence:

  MGNAAAAKKGSEQESVKEFLAKAKEDFLKKWESPAQNTAHLDQFERIKTLGTGSFGRVML
  VKHKETGNHYAMKILDKQKVVKLKQIEHTLNEKRILQAVNFPFLVKLEFSFKDNSNLYMV
  MEYVPGGEMFSHLRRIGRFSEPHARFYAAQIVLTFEYLHSLDLIYRDLKPENLLIDQQGY
  IQVTDFGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALGVLIYEMAAGYPPFF
  ADQPIQIYEKIVSGKVRFPSHFSSDLKDLLRNLLQVDLTKRFGNLKNGVNDIKNHKWFAT
  TDWIAIYQRKVEAPFIPKFKGPGDTSNFDDYEEEEIRVSINEKCGKEFSEF

• Sequence length: 351